CA1 pyramidal neurons of the hippocampus receive excitatory synaptic input onto different dendritic domains: basal dendrites, apical oblique, and apical tuft dendrites. To understand how CA1 neurons carry out their proposed functions in spatial navigation, learning, and memory, it is critical to understand how these neurons integrate synaptic input in these different dendritic domains. Experiments in intact animals have identified functional correlates for synaptic inputs to different dendritic domains, but the biophysics of how these inputs are integrated remains unclear. Here we propose a series of studies designed to better understand the cellular and molecular processes underlying the integration excitatory synaptic inputs in CA1 pyramidal neurons. The primary approach will be to use two-photon uncaging of glutamate to activate dendritic spines in different dendritic domains of neurons in hippocampal slices. Serial-section electron microscopy will also be used to study the structure of dendritic spines and synapses in different dendritic domains. Immunogold labeling combined with serial section electron microscopy will be used to study the densities of synaptic glutamate receptors (AMPA and NMDA receptors) and metabotropic glutamate receptors (mGluR) and acetylcholine receptors (mAChRs) in different dendritic compartments. The function of these synapses and modulatory receptors will be explored using whole-cell patch-clamp recording and two-photon uncaging. Modulation of dendritic integration is likely to be under the control of mGluR and mAChR, which may account for different functional states of the hippocampus during different behavioral states. The results will offer insight into dendritic integration of synaptic inputs at an unprecedented level of structural and molecular detail. Such insights will lead to a better understanding of hippocampal function, which is necessary to understand diseases affecting the hippocampus, such as Alzheimer's disease, schizophrenia, and epilepsy. PUBLIC HEALTH RELEVANCE: We will use, whole-cell patch-clamp recording in hippocampal slices, two-photon uncaging of glutamate, pharmacology, and electron microscopy to study the role of voltage-gated channels in synaptic integration in the dendrites of CA1 neurons. We will determine the mechanisms of integration in four dendritic domains, as well as their modulation by glutamate and acetylcholine. CA1 neurons are among the most abundant in the hippocampus, and they are affected in diseases such as epilepsy and Alzheimer's disease.